Control of Store Operated Calcium Entry by the Spectrin Membrane Skeleton

Depletion of endoplasmic reticulum calcium activates calcium influx across the plasma membrane through store‐operated calcium (SOC) entry channels. SOC entry represents the principal Ca 2+ entry pathway into non‐excitable cells. Despite intensive investigation, mechanisms linking calcium store depletion to activation of SOC entry channels have remained elusive. Multiple different SOC entry channels exist in endothelium, including those that are calcium‐selective and non‐selective. The endothelial I SOC channel is a Ca 2+ ‐selective SOC entry channel to which the transient receptor potential (TRP) proteins TRPC1 and TRPC4 contribute subunits. TRPC4 interacts with protein 4.1 nearby its putative pore region. Indeed, TRPC4 possesses a consensus protein 4.1 binding domain immediately adjacent to a proline rich region. Expression of a chimeric TRPC4 channel (TRPC4) lacking the 51 residues encoding the proline rich region and the protein 4.1 binding domain abolishes I SOC activation. Similarly, transduction of a peptide resembling the TRPC4 proline rich region and protein 4.1 binding domain abolished I SOC activation. These findings suggest that protein 4.1 is an essential component of the I SOC channel gating mechanism, providing a critical cytoskeletal link between calcium store depletion and influx through the TRPC4‐dependent I SOC .